JP2020531593A5

JP2020531593A5 -

Info

Publication number: JP2020531593A5
Application number: JP2020533357A
Authority: JP
Filing date: 2018-08-31
Publication date: 2021-10-14
Anticipated expiration: 2038-08-31

Claims

Formula I:

It is a compound of
During the ceremony
^RN is H or Me;
X ⁴ is selected from CY and N;
X ¹ , X ² , and X ³ are selected from CH and N, respectively, except that ^{none of X 1} , X ² , X ³ , and X ⁴ is N or one of them is N;
Y is H; halo; cyano; R ² , where R ² is selected from CH ₃ , CH ₂ F, CHF ₂ , and CF ₃ ; ethynyl; cyclopropyl; OR ³ , where R ³ is H, CH ₃ , CH ₂ F, is selected from CHF _2, and CF _3; NR ^N1 R ^N2, provided that R ^N1 and R ^N2 is selected from H and CH ₃ independently; COQ ^1, where Q ¹ is C _{1 to 4} replaced by itself OH or CONR ^N1 R ^N2; alkyl, OH, OC _{1 to 4} alkyl, which and NR ^N1 R ^N2 is selected from; NHSO ₂ Q ^3, where Q ³ are are C _{1 to 3} alkyl; pyridyl _{C 5} heteroaryl optionally substituted with a group selected from C _1-3 alkyl which may be; SO ₂ Me; C _1-3 alkyl substituted by NHZ, where Z is H, Me, SO. ₂ Me, or COMe; selected from the group consisting of _{C 1-3 alkyl substituted with OH;}
Cy is selected from pyridyl, oxazolyl, cyclohexyl, and optionally substituted phenyl, provided that the optionally substituted substituent is R ² ; OR ⁵ , where R ⁵ is H, CH ₃ , CH ₂ F, CHF. ₂ , CF ₃ , and cyclopropyl; benzyloxy; halo; cyano; amino; optionally substituted with methyl, CH ₂ OH, CH ₂ OCH ₃ , or = O C ₅ heteroaryl; phenyl; COQ ^5, except Q ⁵ is selected from OH and NR ^N1 R ^N2;; pyridyl substituted by methyl, optionally and CH ₂ OQ ^6, where Q ⁶ is H or Me, is selected from the group consisting of ;
R ¹ is F; phenyl; pyridyl; optionally _{substituted with methyl, CH 2} OCH ₃ , CH ₂ CF ₃ , CHF ₂ , NH ₂ , or = O C ₅ heteroaryl; C ₉ heteroaryl; OH; OMe; OPh; COQ ^4, where Q ⁴ are OH, C _{1 to 3} alkyloxy, NR ^N5 R ^N6, where R ^N5 is selected from H and Me, and R ^{N 6} is itself substituted by CONHMe or also selected from optionally C _{1 to 4} alkyl, or R ^N5 and R ^N6 form a C _{4 to 6} N-containing heterocyclyl group together with the N atom to which R ^N5 and R ^N6 are bonded, (CH ₂₎ _n1 CONR ^N7 ^RN8 , where n1 is 1-3, ^RN7 and ^RN8 are independently selected from H and Me, and O (CH ₂ ) _n2 CONR ^N9 ^RN10 , where n2 is 1 or 3. , ^RN9 and ^RN10 are selected independently of H and Me; (CH ₂ ) _n OQ ⁷ , where n is 1 or 2, Q ⁷ is H or Me; NHCO ₂ Q ⁸ However, Q ⁸ is C _1-3 alkyl; selected from the group consisting of ^{OCONR N5} R ^N6;
R ⁴ may be selected from H, F, and methyl, or R ¹ and R ⁴ may form _{C 4-6} cycloalkyl with the carbon atom to which ^{R 1} and R ^{4 are attached;}
If Cy is pyridyl, cyclohexyl, or substituted phenyl, R ¹ may be further selected from H.

The compound according to claim ¹ , wherein X ^{1, X 2} , and X ³ are CH and X ^{4 is CY.}

(A) X ¹ is N, or (b) X ² is N, or (c) X ³ is N, or (d) X ⁴ is N,
The compound according to claim 1.

Y is Ru is selected from:, according to any one of claims 1 to 3 compounds:
(A) H,
(B) Halo,
(C) I and F,
(D) Cyano,
(E) CH ₃ , CH ₂ F, CHF ₂ , CF ₃ ,
(F) Etinyl and
(G) Cyclopropyl .

Y is Ri OR ³ der, R ³ is Ru is selected from: A compound according to claim 1:
(A) H,
(B) CH ₃ ,
(C) CH ₂ F,
(D) CHF ₂ and
(E) CF ₃ .

Y Ri is NR ^N1 R ^N2 der,
(A) ^{Both RN1} and ^RN2 are H,
(B) ^{Both RN1} and ^RN2 are Me, or
(C) R ^N1 is Ru and R ^N2 is Me der H, and A compound according to any one of claims 1 to 3.

Y is COQ Ri ¹ der, Q ¹ is Ru is selected from: A compound according to claim 1:
(A) C _1-4 alkyl,
(B) OH,
(C) OC _1-4 alkyl,
(D) NR ^N1 R ^N2 , where
(I) ^{Both RN1} and ^RN2 are H,
(Ii) ^{Both RN1} and ^RN2 are Me, or
(Iii) ^RN1 is H and ^RN2 is Me .

Y is Ri NHSO ₂ Q ³ der, Q ³ is Ru C _1-3 alkyl der compound according to any one of claims 1 to 3.

The compound according to any one of claims 1 to 3, wherein Y is pyridyl.

Y is Ri Ah at C ₅ heteroaryl optionally substituted, the substituent on the C ₅ heteroaryl, unsubstituted C _{1 to 3} alkyl, C _{1 to 3} alkyl substituted by OH, and CONR ^N1 R ^N2 Ru is selected from C _1-3 alkyl substituted by a compound according to any one of claims 1 to 3.

The compound according to any one of claims 1 to 3, wherein Y is SO _{2 Me.}

Y is C _{1 to 3} alkyl substituted by NHZ, where Z is H, Me, SO ₂ Me, or COMe der is, or Y is Ru C _{1 to 3} alkyl der substituted by OH, claim 1 The compound according to any one of 3 to 3.

R ¹ is Ru is selected from:, according to any one of claims 1 to 12 compounds:
(A) H,
(B) F,
(C) Phenyl,
(D) Pyridil,
_{(E) C 5} heteroaryls optionally substituted with methyl, CH ₂ OCH ₃ , CH ₂ CF ₃ , CHF ₂ , NH ₂ , or = O.
(F) C ₉ heteroaryl,
(G) OH,
(H) OMe,
(I) OPh,
(J) COQ ⁴ ,
(K) (CH ₂ ) _n OQ ⁷ ,
(L) NHCO ₂ Q ⁸ , where Q ⁸ is C _1-3 alkyl and
(M ) OCONR ^N5 ^{R N6} .

R ⁴ is Ru is selected from:, according to any one of claims 1 to 13 compounds:
(A) H,
(B) F and
(C) Methyl .

R ¹ and R ^4, C _{4 to 6} to form a cycloalkyl together with the carbon atom to which R ¹ and R ⁴ are attached, a compound according to any one of claims 1 to 12.

Cy is Ru is selected from:, according to any one of claims 1 to 15 compounds:
(A) Pyridil,
(B) Oxazolyl,
(C) Cyclohexyl and
(D) Unsubstituted phenyl .

The compound according to any one of claims 1 to 15 , wherein Cy is a phenyl having a single substituent.

The phenyl substituent
a) CH ₃ ,
b) CH ₂ F,
c) CHF ₂ ,
d) CF ₃ ,
e) OCH ₃ ,
f) OCH ₂ F,
g ) OCHF ₂ ,
h) OCF ₃ and
i) The compound of claim 17 , selected from O-cyclopropyl.

Substituents of the phenyl Ru is selected from: The compound of claim 17:
(A) benzyloxy,
(B) Halo,
(C) Cyano,
(D) NH ₂ ,
_{(E) C 5} heteroaryl, optionally substituted with methyl, CH ₂ OH, CH ₂ OCH ₃ , or = O.
(F) Phenyl,
(G) Pyridyl, optionally substituted with methyl,
(H) CO ₂ H,
(I) CO ₂ Me,
(J) CONR ^N1 R ^N2 , where
i) ^{Both RN1} and ^RN2 are H, or
ii) ^{Both RN1} and ^RN2 are Me, or
iii) ^RN1 is H and ^RN2 is Me,
(K) CH ₂ OH and
(L) CH ₂ OME .

^One of claims 1 to 12 , wherein R 1 is H and Cy has a _{substituent selected from OCHF 2} _{and a C 5} heteroaryl group selected from oxazolyl, pyrazolyl, and triazolyl at the 2-position. The compound described in.

The compound according to any one of claims 1 to 12 , wherein R ¹ is selected from oxazolyl, methyl oxadiazolyl, and pyrazolyl, and Cy does not have a substituent at the 2-position.

The compound according to any one of claims 1 to 21 , for use in a therapeutic method.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

The compound according to any one of claims 1 to 21 or the pharmaceutical composition according to claim 23 for use in the treatment of cancer.

The compound or pharmaceutical composition according to claim 24 , wherein the treatment is for co-administration or sequential administration with radiation therapy and / or chemotherapy.